Case 5 Roots of Informed Consent

The Spanish-American War began and ended in 114 days. The U.S. victory appeared to have been won fairly cheaply, with casualties only in the hundreds. But, that was just the beginning. As American soldiers took control of the island of Cuba, they, like all other newcomers to Cuba, were confronted with a range of tropical diseases-typhoid, malaria, yellow fever, dengue fever-toward which they had no natural immunity. For every one soldier who died in the war, hundreds quickly died of disease.

Typhoid and malaria were brought under control in a short time, but yellow fever was not. This disease had been endemic in Cuba since 164

Cubans typically contracted yellow fever early in life and either died or developed life-long protection. The disease always followed the same pattern. The first three days involved fevers and chills. Then, the person felt much better and seemed to be getting well. But, on the fourth day, the person's teeth began to chatter, fevers spiked higher than before, and chills were chillier. The skin turned yellow, blood oozed from patches inside the mouth, and black vomit (a mixture of blood and digestive juices) spewed forth. Proteins leaked into the urine, the liver and kidneys shut down, violent hiccups began, delirium set in, then coma, and finally death. From start to unhappy finish, the disease lasted just six to nine days. About 30% of people who contracted yellow fever died.

So, shortly after the war ended, the Surgeon General of the United States, George Miller Sternberg, organized a medical commission to tackle the disease. Sternberg appointed Walter Reed as the commission's head. Reed arrived in Cuba in June, 1900, and there he and three other researchers-Jesse Lazear, Aristides Agramonte, and James Carroll-began their investigations.

One major barrier for studying the disease was that it only affected people. With no animal model to use, the researchers were obliged to do all their experiments on people. In 1897, Giuseppe Sanarelli, an Italian bacteriologist working at the Pasteur Institute in Paris, had been criticized for his yellow fever experiments on five unsuspecting subjects, three of whom died. One critic labeled Sanarelli's experiments "ridiculous." But the Canadian physician Sir William Osler said: "To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man's sanction, is not ridiculous, it is criminal."

The members of the commission concluded that, if they were going to experiment with people, they should be willing also to experiment on themselves. Agramont was a native of Cuba, had battled the disease as a child, and was no longer susceptible, but the other three could be subjects in the experiments.

Little was known at the time about the cause or transmission of yellow fever, but mosquitoes were suspect. Could a mosquito that bit a sick person then transmit the disease by biting someone who was well? The timing of both bites proved critical. The mosquito-specifically, a female Aedes aegypti mosquito-needed to drink its blood meal from a sick person during the first three days of infection. Then, a period of two to three weeks was required for the agent of the disease to mature and move to the mosquito's salivary glands. With the mosquito's next blood meal, that agent then could be injected into the next unlucky victim.

The experiments were crude but direct. A test tube containing a mosquito was inverted onto the arm of someone who was sick. The mosquito sank its six sharp stilettos into the flesh, found a vein or artery, and drank a blood meal. After two weeks, the test tube containing the mosquito was inverted onto the arm of a healthy subject. Researcher and subject then watched as the mosquito once again sank its stilettos through the flesh and into the bloodstream. There, it once again exchanged fluids with its host, injecting salivary juices and the viruses that caused yellow fever into the blood stream while drinking another blood meal.

After a few false starts, Lazear's disease-transmission experiments began to work. Carroll became dangerously ill and almost died. William Dean, a soldier who volunteered, also became infected, but his disease was less severe. Then, Lazear inverted the test tube onto his own arm. For once, he got the timing right-he had unsuccessfully tried to infect himself before-contracted yellow fever, and died. Lazear kept a diary detailing his experiments, so it was possible for Reed and others to reconstruct exactly what he had done and build on his experimental "success."

After Lazear's unexpected death, Reed created the first written "informed consent" document, which outlined the risks of the experiments and their possible benefits. Those who agreed to be subjects in the experiments had to sign the forms. The American military governor of Cuba provided funds to set up a proper research laboratory-seven tents and a flagpole flying an American flag-and funds were also available to pay volunteers. The American soldiers who participated did not get paid but the Spanish immigrants who volunteered each received $100 in gold to participate and $100 more if they got sick. For volunteers, the risks of the yellow fever experiments even seemed worth taking, because, being new to the island, they were likely to contract the disease in any case. At least in an experiment, they would get rapid and decent medical treatments.

All told, 29 people contracted the disease while participating in the commission's experiments and five died. One soldier never fully recovered from participating, and he was incapacitated for the rest of his life. When the plight of this soldier, Private John Kissenger, was discovered (in 1926), a committee raised money to buy a 'dream home' for the "yellow fever martyr."

After mosquitoes were implicated in the transmission of the disease, a thorough mosquito eradication program began, and yellow fever was wiped out in Cuba.

Included References

Bulletin Hist. Med 1977, 51, 87 (Reed's story)

Additional Resources

Microbe Hunters, Paul de Kruif, Chapter 11, A Harvest/HBJ Book, San Diego, 1926.
Journal of the American Medical Association, 1940, 115:1943 and 1563.
Guinea Pig Doctors, Jon Franklin, John Sutherland, Morrow, NY, pages 183-226, The Forgotten Hero of Yellow Fever, 1984.
Film: Yellow Jack: Walter Reed in Cuba, 1938 Metro-Goldwyn-Mayer (based on play which was based on deKruif book)
Subjected to Science, Susan Lederer, Johns Hopkins University Press, Baltimore, 1995.
Undue Risk: Secret State Experiments on Humans, Jonathan D. Moreno, W.H. Freeman and Co. NY, 1999.
Acres of Skin, Allen Hornblum, Routledge, NY, 1998.

Aims

Students should understand the following:

History of informed consent
Rights of volunteers in medical research
Balance between individual benefit and societal benefit in research
Design of clinical trials
How mosquitoes transmit diseases
Causes and symptoms of yellow fever
Endemic disease
Epidemic disease
Obligations, duties and autonomy for soldiers
Obligations, duties and autonomy for civilian research subjects
Obligations, duties and autonomy for doctors and researchers

Topics for Discussion/Written Assessment

How do mosquitoes transmit diseases?
What other infectious agents do mosquitoes transmit besides the yellow fever agent?
What is the "second host" for an infectious organism? What is the "natural history" of an infectious disease?
Paul De Kruif wrote about Walter Reed's yellow fever experiments in his book The Microbe Hunters.
"Walter Reed let it be known to the American soldiers in Cuba that there was another war on, a war for the saving of men-were there men who would volunteer? Before the ink was dry on the announcements Private Kissenger of Ohio stepped into his office, and with him came (civilian clerk) John J. Moran?"You can try it on us, sir!" they told him. Walter Reed was a thoroughly conscientious man. "But, men, do you realize the danger?" And he told them of the headaches and the hiccups and the black vomit. ..."We volunteer solely for the cause of humanity and in the interest of science." Then Walter Reed told them of ? the handsome sum they would get ? "The one condition on which we volunteer, sir," (they) said, "is that we get no compensation for it." ? Then great days came to Reed and Carroll and Agramonte-for, if they weren't exactly overrun with young Americans who were ready to throw away their lives in the interest of science-and for humanity, still there were ignorant people, just come to Cuba from Spain, who could very well use two hundred dollars. ? "Spanish immigrants," or I could call them Man 1, 2, 3, and 4-just as microbe hunters often mark animals: "Rabbit 1, 2, 3, and 4-" anyway ? they earned their two hundred dollars ? If they hadn't been ignorant immigrants-hardly more intelligent than animals, you might say-they might have been bored, because nothing had happened to them excepting the stabs of silver-striped she-mosquitoes ? " (pages 296-297).
Comment on DeKruif's style of writing about the various 'players'-Reed, the soldiers, and the Spanish immigrants. How respectful was he of each group?
How voluntary is the 'consent' likely to be of prisoners who agree to be in clinical trials? In 1951, Dr. Albert Kligman treated some patients for athlete's foot at Pennsylvania's Holmesburg prison. At the time, the prison housed some 1200 prisoners. "I began to go to the prison regularly," said Kligman, "although I had no authorization. It was years before the authorities knew that I was conducting various studies on prisoner volunteers. Things were simpler then. Informed consent was unheard of. No one asked me what I was doing. It was a wonderful time." Kligman was studying how various agents (including probably LSD, sunscreens, dyes, and isotopes) affected, protected, and/or penetrated the skin. "All I saw before me were acres of skin. It was like a farmer seeing a fertile field for the first time." What happens when the subjects of experiments are objectified in the way that Kligman objectified the prisoners? Kligman continued his experiments at Holmesburg for 30 years. Said one volunteer: "Many (prisoners) compromised the experiments" (by taking the soaked patches off their skin when they went to their cells). "Those doctors were running a game on us, so we ran a game on them." What was wrong with Kligman's approach? How reliable are the data, considering that the prisoners were not interested in compliance?
What reasons would you give for volunteering for medical research? What reasons would you give for not volunteering?
Have you ever participated in medical research? If so, what was the experiment and what happened? Design an experiment in which you would be willing to be a subject.
When the members of the yellow fever commission decided to experiment on themselves, what reasoning and principles guided their decisions?
What are the steps in the review process for medical experimentation?
Should self experimentation be subjected to the same review process as experiments on others? Why?
When volunteers agree to participate in a study, they are asked to sign a consent form, which outlines the purpose, design, risks and benefits, and possible outcomes of the experiment. What responsibilities do researchers have to make sure that volunteers are truly informed about the experiment? How can they find out if the subjects really understand what they are volunteering to do?

Extension Questions for Further Investigation

Is self experimentation a good or bad idea? Why? What about experiments on lab workers, nurses, doctors, and others who are familiar with the experiments? What are the advantages of using those who are knowledgable about the studies? What are the disadvantages?
What other examples of self experiments can you find? What happened in each case? From your research, what advantages and disadvantages do you see in self experimentation?
What other infectious agents do mosquitoes transmit besides the agent that causes yellow fever?
Sometimes transmission of a disease-causing agent by an insect vector involves a second host. What organisms are transmitted this way? What diseases do they cause? What happens to the agent of disease in each host animal?
What are Koch's Postulates? How do Koch's Postulates prove that a given organism causes a given disease?
In what areas of the world is yellow fever still a problem?
Why was yellow fever endemic in Cuba but not present at all 90 miles north in the United States?
What are the differences between diseases that are endemic and those that are epidemic?
Walter Reed never actually participated in the yellow fever studies, even though he had agreed to along with his colleagues. Find out what Reed was doing when the others were being bitten by mosquitoes.
In 1999, U.S. Air Force Major Sonnie Bates refused to be vaccinated against anthrax. Bates cited a rise in unusual symptoms and illnesses (bone and joint pain, memory loss, thyroid damage, liver damage, cysts around the heart, autoimmunity) in members of his squadron after they began taking the shots. Anthrax is a deadly disease that is considered a likely component of biological weaponry. By 2000, Bates was facing a court martial. Examine the subsequent events in the case.
Tuberculosis has become a major public health problem in recent years. Under what circumstances, if any, would it be appropriate to quarantine those with the disease who do not agree to take their medicines and therefore are endangering the health of others?
Under what circumstances, if any, would you find it appropriate to waive the informed consent requirements in a clinical trial?

Topics for Teacher Preparation

How mosquitoes transmit the agents of disease
Informed consent
Host animal
Insect vector
Rights of volunteers in medical experiments
Cause of yellow fever
Endemic disease
Epidemic disease